Oral dosage forms for oxygen-containing active agents and oxyl-containing polymer

ABSTRACT

The disclosed invention is drawn to pharmaceutical tablets that provide delivery of active agents having at least three oxygen-containing groups, as well as a second active ingredient. Non-limiting examples of three oxygen-containing group active agents include guaifenesin, codeine, hydrocodone, and their pharmaceutically acceptable salts. In one embodiment, a pharmaceutical tablet for oral administration once every 12 hours is provided. The tablet includes a first active agent that is a tri-oxy active agent, a second active agent, and a release rate controlling non-ionic oxyl-containing hydrophilic polymer. The total oxyl content of the hydrophilic polymer in the tablet is about 4×10 −4  moles to about 2.0×10 −3  moles.

This application is a continuation of U.S. patent application Ser. No.13/342,883, filed Jan. 3, 2013, which is herein incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to oral dosage forms containingcombination of pharmaceutical active agents for treating cough andassociated methods of treatment and manufacture. Accordingly, thisinvention involves the fields of chemistry, pharmaceutical sciences,medicine and other health sciences.

BACKGROUND OF THE INVENTION

Tri-oxy active agents (drugs having at least three differentoxygen-containing groups) such as guaifenesin, codeine and hydrocodoneare used to treat cold and cough as well as other related symptoms.Often, cold, cough, allergies, and other similar conditions can requiretreatment with multiple active agents in order to simultaneouslyalleviate multiple symptoms. For example, combinations of active agentssuch as codeine or hydrocodone with a mucolytic or a decongestant or ananti-tussive have been used for management of cold, cough and flusymptoms. However, these combinations are primarily available asinconvenient liquids which are prone to dosing errors and which requirefrequent dosing in order to provide consistent and continuous symptomrelief. Commercially available combination products tend to beshort-acting and often require dosing every four, six or eight hours.The need for frequent dosing and the re-emergence of symptoms betweendoses often make sleeping difficult, which in turn can delay therecovery process. Moreover, the combination dosage forms must meet eachactive agent's own unique pharmacokinetic requirement for symptom orco-symptom relief.

Guaifenesin (glyceryl guaiacolate, GGE) is a widely used expectorantthat assists in loosening phlegm (mucus) and thins bronchial secretionsto make cough more productive. The structure of guaifenesin is generallyshown as:

Guaifenesin is thought to act by increasing the volume and reducing theviscosity of secretions in the trachea and bronchi. It is also reportedto stimulate the flow of respiratory tract secretions allowing ciliarymovement to carry the loosened secretions upward toward the pharynx.Guaifenesin has a plasma half-life of about one hour. GGE is commonlyavailable as an immediate release tablet (200 mg and 400 mg strengths)requiring frequent dosing such as once every four hours.

Codeine (3-methylmorphine) is an opiate used widely for its antitussive(cough suppression) and analgesic properties. Its structure is generallyshown as:

Codeine helps in temporary control of cough caused by minor throat andbronchial irritation as occurs with common cold or inhaled irritants.The recommended antitussive codeine dose in adults and children 12 yearsof age and above is 10 to 20 mg codeine administered every 4 to 6 hoursnot to exceed 120 mg/day. The reported a plasma half-life for codeine isabout 2.5-3 hours. It is more commonly available as immediate releasedosage form that requires frequent dosing.

Hydrocodone is a narcotic pain reliever and a cough suppressant and itsstructure is generally shown as:

Hydrocodone is an opioid derived from codeine and is recognized as bothan effective analgesic and antitussive agent. It is generally consideredto be one of the potent and effective antitussive drugs and is believedto act, at least in part, by a direct depressant effect on a coughcenter in the medulla and to a lesser degree the respiratory center. Therecommended adult hydrocodone bitartrate dosage for the symptomaticrelief of cough is 5 mg (as hydrocodone bitartrate) every 4 to 6 hoursas needed, not to exceed 30 mg in 24 hours. Children 6 to 12 years ofage should be administered ½ the adult dose, not to exceed a total of 15mg drug in 24 hours. It is reported to have a plasma half-life of about3.8 to 6 hours. It is more commonly available as immediate releasedosage form that requires frequent dosing.

Pseudoephedrine is a sympathomimetic drug of the phenethylamine andamphetamine chemical classes. It is found as a hydrochloride or sulfatesalt in many over-the-counter preparations more commonly as a singleingredient formulation. It is generally indicated for temporary reliefof nasal and/or sinus congestion due to the common cold, hay fever orother upper respiratory allergies. The typical dose for adults andchildren 12 years of age is 60 mg to 120 mg.

Chlorpheniramine is a propylamine antihistamine (H₁-receptor antagonist)that also possesses anticholinergic and sedative activity. It preventsreleased histamine from dilating capillaries and causing edema of therespiratory mucosa.

Chlorpheniramine maleate is commonly available in immediate releasedosages as an over-the-counter anti-allergy drug. Following oraladministration of chlorpheniramine the peak plasma concentration isreached in 2-3 hours and its duration of effect lasts for 4-6 hours,therefore requiring frequent dosing. The oral dose in adults andchildren 12 years of age and older is typically 4 mg chlorpheniraminemaleate every 4 to 6 hours.

Dextromethorphan hydrobromide monohydrate (C₁₈H₂₅NO.HBr.H₂O) is acentrally acting antitussive agent which elevates the threshold forcoughing. It has no analgesic or addictive properties. Its dose is 10 to30 mg every 4 to 8 hours. Dextromethorphan exerts its effect in 15 to 30minutes after oral administration and its duration of action is forapproximately three to six hours, hence requiring frequent dosing.

Phenylephrine is a potent decongestant agent commonly used for temporaryrelief of nasal congestion associated with allergy or head coldssymptoms, etc. Following oral administration, phenylephrine exerts itseffect in 15 to 30 minutes and its effect persists for up to 4 hours,therefore requiring frequent dosing. The usual adult dose ofphenylephrine is 10 to 20 mg orally every 4 hours as needed.

Most long acting oral dosage forms currently available to treat theabove-recited conditions contain only one active agent, and typicallyrequire coating or bi-layering to enable various controlled or sustainedrelease including biphasic release of the active.

Oxyl-containing polymers (having oxygen-containing groups) such asmethacrylates, carbomers, hypromellose (HPMC), etc. have been used toenable slow release dosage forms having a single tri-oxy or non-tri-oxyactive. As reported for a single-layer matrix tablet of a non-tri-oxyactive such as chlorpheniramine, an HPMC polymer (Methocel K4M) toactive ratio of about 1:1 provides a time to 50% in vitro drug releaseof about 3.5 hours. However, such very slow release profile isunsuitable for a 12 hour dosing therapy of tri-oxy actives to allowsleeping through the night and without excessive daytime grogginess.

Use of oxyl-containing non-ionic hydrophilic polymers (e.g. HPMC) havealso been reported to formulate a single di-oxy active (having twodifferent oxygen-containing groups) such as propranolol HCl into amatrix tablet, wherein a HPMC (Methocel K4M) to active agent ratio is1:0.3 by weight, and which provides a time to 50% drug release in vitroof about 4 hours. However, such a slow release profiles for tri-oxyactives is unsuitable for a 12 hour dosing therapy.

Due to tremendous safety liability associated with deviations fromacceptable peak blood concentrations, many tri-oxy active agents, suchas narcotics like codeine and hydrocodone, require stable blood levelsupon oral dosing. For a solid dosage form (tablet, capsules etc.)containing multiple actives with a hydrophilic polymer, the design andmanagement of the dosage form performance for a given intended usebecomes increasingly challenging. This is especially true with regardsto efficacy, release, and pharmacokinetic requirements, which can befurther complicated for each active due to its distinct physiochemicaland biological properties. Additionally, food interactions with an oraldosage form upon ingestion can produce unacceptable higher bloodconcentrations of actives, especially from a longer acting product whichhas higher active strength per dosage unit relative to an immediaterelease dosage form. It is noteworthy that regulatory concerns relatedto food effects of a bilayer tablet containing ionic polymer ofguaifenesin and codeine have been reported in the literature.

To date, there appear to be no known teachings that enable a combinationmatrix tablet containing at least one tri-oxy active, such asguaifenesin or a codone, that upon single administration of thecombination tablet of two pharmacologically different actives arereleased in an optimal manner, individually and collectively, and thatenables optimal blood levels of each active as required for twice-a-daydosing therapy for regulatory approval purposes.

SUMMARY OF THE INVENTION

The present inventors have recognized a benefit to providing a tri-oxyactive containing pharmaceutical tablet that is a matrix tabletformulated for dosage every twelve hour and which does not have negativefood effects. Moreover, it has been surprisingly found that by includingcertain levels of at least one tri-oxy active agent in anoxyl-containing non-ionic hydrophilic polymer based matrix tablet, thereexists a unique optimal oxyl content composition that enables a 12 hourproduct having no food effect.

Accordingly, the present disclosure is drawn to combinationpharmaceutical solid dosage forms comprising at least one tri-oxy activeagent, a second active agent, and optionally, a third active agent. Thedosage form is formulated for oral dosing once every 12 hours. Thetablet can include a first active agent that is a tri-oxy active agent,a second active agent, and a release rate controlling non-ionicoxyl-containing hydrophilic polymer. The total oxyl content of thehydrophilic polymer in the tablet is from about 4×10⁻⁴ moles to about2.0×10⁻³ moles. In one embodiment, a pharmaceutical matrix tablet fororal administration once every 12 hours is provided. Related methods ofuse and treatment are also provided. In one aspect, a single-doseadministration of one or more tablets to a subject under fastedconditions can provide a mean C_(max) for each of the first active agentand the second active agent that is about 70% to about 135% of arespective mean C_(max) provided by administering an immediate releaseoral dosage, as a combination or respective single active dosage form,to a subject under fasted conditions every 4 to 6 hours over a 12 hourtime period, wherein cumulative dosage amounts administered over the 12hour time period of each active agent from the immediate release dosageforms are equivalent to the respective amount of each active agent inthe pharmaceutical tablet.

In another embodiment, a combination pharmaceutical solid dosage formsis provided that includes at least one tri-oxy active agent, a secondactive agent, and optionally, an third active agent. The dosage form isformulated for oral dosing once every 12 hours. The tablet can include afirst active agent that is a tri-oxy active agent, a second activeagent, and a release rate controlling non-ionic oxyl-containinghydrophilic polymer. The total oxyl content of the hydrophilic polymerin the tablet is from about 4×10⁻⁴ moles to about 2.0×10⁻³ moles. In oneembodiment, a pharmaceutical matrix tablet for oral administration onceevery 12 hours is provided. Related methods of use and treatment arealso provided. In one aspect, a single-dose administration of one ormore tablets to a subject under fasted conditions can provide a meanC_(max) for each of the first active agent and the second active agentthat is about 70% to about 135% of a respective mean C_(max) provided byadministering the same oral dosage to a subject under fed over a 12 hourtime period, wherein cumulative dosage amounts administered over a 12hour time period.

In another embodiment, a pharmaceutical solid dosage form for dosingonce every 12 hours is provided. The solid dosage form is a matrixtablet and can include a first active agent that is a tri-oxy activeagent, a second active agent, and a release rate controlling non-ionicoxyl-containing hydrophilic polymer. The tablet is formulated such thatwhen placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of0.1 N hydrochloric acid solution in water at 37° C., about 50 wt % ofthe first active agent is released in about 1.5 hours to about 3.2hours. The ratio of the amount of first active released from the tabletto the amount of second active agent released at 1 hour and at 4 hoursis between about 0.7:1 and about 1.3:1.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a plot of the release profile of several embodimentformulations of the present invention as well as a comparative example.

FIG. 2 is a plot release profiles of the actives from some of therepresentative examples as well as a comparative example.

FIG. 3 is a plot of release profiles of the actives from somerepresentative examples and comparative examples.

DETAILED DESCRIPTION

Before the present pharmaceutical tablets and related methods of use aredisclosed and described, it is to be understood that this invention isnot limited to the particular process steps and materials disclosedherein, but is extended to equivalents thereof, as would be recognizedby those ordinarily skilled in the relevant arts. It should also beunderstood that terminology employed herein is used for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

It should be noted that, the singular forms “a,” “an,” and, “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to “an excipient” includes reference to oneor more of such excipients, and reference to “the carrier” includesreference to one or more of such carriers.

DEFINITIONS

As used herein, the term “treatment,” when used in conjunction with theadministration of oral dosage forms containing guaifenesin and a codone(such as codeine, hydrocodone etc), refers to the administration of theoral dosage forms to subjects who are either asymptomatic orsymptomatic. In other words, “treatment” can both be to reduce oreliminate symptoms associated with a condition or it can be prophylactictreatment, i.e. to prevent the occurrence of the symptoms. Suchprophylactic treatment can also be referred to as prevention of thecondition.

As used herein, the terms “formulation” and “composition” are usedinterchangeably and refer to a mixture of two or more compounds,elements, or molecules. In some aspects the terms “formulation” and“composition” may be used to refer to a mixture of one or more activeagents with a carrier or other excipients. Furthermore, the term “dosageform” can include one or more formulation(s) or composition(s) providedin a format for administration to a subject. When any of the above termsis modified by the term “oral” such terms refer to compositions,formulations, or dosage forms formulated and intended for oraladministration to subjects.

A temperature processing aid is a compound that, when added to theformulations of the present disclosure, can act to impart handlingflexibility with respect to processing temperature. As used herein,“active agent,” “bioactive agent,” “pharmaceutically active agent” and“drug” may be used interchangeably to refer to an agent or substancethat has measurable specified or selected physiologic activity whenadministered to a subject in an effective amount. More specifically, asused herein, a “tri-oxy active agent” or “tri-oxy active” has at leastthree different types of oxygen-containing groups in the “parent” orbasic molecular structure. The oxygen-containing group can be a carbonylor ketone (C═O) group, a methoxy or methoxyl (—OCH₃) group, an ether(—O—) group, or hydroxy or hydroxyl (—OH) group. For example, in oneembodiment the tri-oxy active can have at least one methoxyl group, atleast one ether group, and at least one carbonyl or hydroxyl group.

In one embodiment, the tri-oxy active suitable for this invention isselected from the group comprising guaifenesin, codeine, hydrocodone,guaiacolsulfonate, carbetapentane, methscopolamine, and theirpharmaceutical acceptable salts, hydrates, solvates and polymorphs. In aspecific embodiment, the tri-oxy active suitable for this invention isselected from the group comprising guaifenesin, codeine, hydrocodone,guaiacolsulfonate and their pharmaceutical acceptable salts, hydrates,solvates and polymorphs.

Similarly, as used herein, a “non-tri-oxy” active agent is apharmaceutically active agent that contains less than three differentoxygen-containing groups. In one embodiment, the non-tri-oxy active canhave only one oxygen-containing group. In another embodiment, thenon-tri-oxy active does not have any oxygen-containing group.

As used herein, “decongestants” are a class of active agents thatinduces vasoconstriction of the blood vessels in the nose, throat, andparanasal sinuses, which results in reduced inflammation (swelling) andmucus formation in these areas. These actives are commonly used in thetreatment of cough/cold symptoms. Non-limiting examples of suitabledecongestants of are ephedrine, levo-methamphetamine, phenylephrine,phenylpropanolamine, propylhexedrine, pseudoephedrine, synephrine,levonordefrin, mephentermine, tuaminoheptane, tymazoline, and theirpharmaceutically acceptable salts.

As used herein, the term “non-ionic oxyl-containing hydrophilic polymer”is an uncharged polymer that contains at least hydroxyl (—OH) andmethoxyl (—OCH₃) groups in its basic monomer structure; the polymerswells/gels and eventually dissolves in water. The number of each ofthese groups in the polymer determines the rate and extent of itshydration/gelling in an aqueous medium.

Accordingly, the “methoxyl content” or “methoxy content” of the polymeris the total methoxyl groups in the polymer and can be expressed asmoles percent (moles %). Similarly, the “hydroxyl content” of thepolymer is the total hydroxyl groups in the polymer and can be expressedas moles %. For example, one mole of the Hypromellose 2208, is reportedto contain approximately 22 mole % methoxyl groups and 8 mole % hydroxylgroups. In other words, the methoxyl groups and hydroxyl groupsconstitute about 22% and 8% of the molecular weight, respectively.

As used herein, the “total oxyl content of the polymer” is the sum ofthe methoxyl and hydroxyl contents in the molecule, and can be expressedin terms of moles. It can also be expressed in terms of moles per dosageunit (example, a tablet), which is calculated based on the amount ofthat specific polymer present per dosage unit.

The total oxyl content, methoxyl and hydroxyl contents of the non-ionicoxyl-containing hydrophilic cellulose polymer in the tablet of thecurrent invention can be calculated by the following equations:

${{Total}\mspace{14mu} {Oxyl}\mspace{14mu} {Content}\mspace{14mu} {in}\mspace{14mu} {moles}} = {\left( \frac{{Weight}\mspace{14mu} {of}\mspace{14mu} {polymer}\mspace{14mu} {in}\mspace{14mu} {tablet}\mspace{14mu} {in}\mspace{14mu} {grams}}{{Molecular}\mspace{14mu} {Wt}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {Polymer}} \right)*\left\lbrack {3 + \left\{ {{Dp}*\left( {A + 1} \right)} \right)} \right\rbrack}$${{Total}\mspace{14mu} {Methoxyl}\mspace{14mu} {Content}},{{{in}\mspace{14mu} {moles}} = {\left( \frac{{Weight}\mspace{14mu} {of}\mspace{14mu} {polymer}\mspace{14mu} {in}\mspace{14mu} {dosage}\mspace{14mu} {form}\mspace{14mu} {in}\mspace{14mu} {grams}}{{Molecule}\mspace{14mu} {Wt}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {Polymer}} \right)*\left( {D_{p}*A} \right)}}$${{Total}\mspace{14mu} {Hydroxyl}\mspace{14mu} {Content}},{{{in}\mspace{14mu} {moles}} = {\left( \frac{{Weight}\mspace{14mu} {of}\mspace{14mu} {polymer}\mspace{14mu} {in}\mspace{14mu} {dosage}\mspace{14mu} {form}\mspace{14mu} {in}\mspace{14mu} {grams}}{{Molecular}\mspace{14mu} {Wt}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {Polymer}} \right)*\left( {D_{p} + 3} \right)}}$

Wherein, Dp=Degree of Polymerization depending on the grade of polymer,A=degree of substitution of Methoxyl group in the polymer and A=1.4 and1.9 for Hypromellose 2208 and Hypromellose 2910, respectively. The abovevalues for Dp and A is typical for a given type of hypromellose and canbe obtained from the manufacturer's technical sheets/certificates.

By way of example, consider a tablet containing 100 mg of a Hypromellose2208 of 4000 cP viscosity grade. The total oxyl, methoxyl and hydroxylcontents for the polymer can be calculated as shown below:

From the literature, Hypromellose 2208 has a methoxyl substitution of1.4, a degree of polymerization of 460 and a molecular wt of 86,000g/mol. Using these values in the above said equations, the followingresults are obtained:—

$\begin{matrix}{{{Total}\mspace{14mu} {oxylcontent}} = {\left( \frac{0.1}{86,000} \right)*\left\lbrack {3 + \left\{ {460*\left( {1.4 + 1} \right)} \right\}} \right\rbrack}} \\{{1.29*10^{- 03}\mspace{14mu} {moles}}}\end{matrix}$ $\begin{matrix}{{{Total}\mspace{14mu} {Methoxyl}\mspace{14mu} {Content}} = {\left( \frac{0.1}{86,000} \right)*\left( {460*1.4} \right)}} \\{= {7.49*10^{- 04}\mspace{14mu} {moles}}}\end{matrix}$ $\begin{matrix}{{{Total}\mspace{14mu} {Hydroxyl}\mspace{14mu} {Content}} = {\left( \frac{0.1}{86,000} \right)*\left( {460 + 3} \right)}} \\{= {5.38*10^{- 04}\mspace{14mu} {moles}}}\end{matrix}$

As used herein, the “total molar oxygen containing groups of the active”is the sum of the oxygen containing groups in the molecule, and can beexpressed in terms of moles. It can also be expressed in terms of molesper dosage unit (example, a tablet), which is calculated based on theamount of the oxygen containing groups for that specific active presentper dosage unit.

The “total molar oxygen containing groups of the active” in the tabletof the current invention can be calculated by the following equations:

${{Total}\mspace{14mu} {molar}\mspace{14mu} {oxygen}\mspace{14mu} {containing}\mspace{14mu} {groups}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {active}} = {\left( \frac{{Weight}\mspace{14mu} {of}\mspace{14mu} {Active}\mspace{14mu} {in}\mspace{14mu} {dosage}\mspace{14mu} {form}\mspace{14mu} {in}\mspace{14mu} {grams}}{{Molecular}\mspace{14mu} {Wt}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {Active}} \right)*A}$

Wherein A is the number of oxygen containing groups in the “parent” orbasic molecular structure. For example, for guaifenesin, A=4; forcodeine phosphate, A=3; for hydrocodone bitartrate, A=3. The weight ofactive in the dosage form is the actual weight of the active used. Themolar weight is the weight of one mole of the active expressed in grams.For the purpose of the above calculation, if a salt form is used in thedosage form, the weight of active used and the molar weight should be ofthe corresponding salt only.

As an example, for a tablet having 30 mg (0.03 g) of Codeine Phosphate,(molecular weight=397.37; number of oxygen-containing groups in the“parent” or basic molecular structure=3) the total molar content ofoxygen containing groups can be calculates as

${{Total}\mspace{14mu} {molar}\mspace{14mu} {oxygen}\mspace{14mu} {containing}\mspace{14mu} {groups}\mspace{14mu} {in}\mspace{14mu} 30\mspace{14mu} {mg}\mspace{14mu} {Codeine}\mspace{14mu} {Phosphate}} = {{\left( \frac{0.03}{397.37} \right)*3} = {2.26*10^{- 04}\mspace{14mu} {Moles}}}$

Similarly, for a tablet having 600 mg (0.6 g) of Guaifenesin (molecularweight=198.22; number of oxygen-containing groups in the “parent” orbasic molecular structure=4), the total molar content of oxygencontaining groups can be calculated as:

${{Total}\mspace{14mu} {molar}\mspace{14mu} {oxygen}\mspace{14mu} {containing}\mspace{14mu} {groups}\mspace{14mu} {in}\mspace{14mu} 600\mspace{14mu} {mg}\mspace{14mu} {Guaifenesin}} = {{\left( \frac{0.6}{198.22} \right)*4} = {1.21*10^{- 02}\mspace{14mu} {Moles}}}$

Calculation of ratio of the total molar content of oxyl groups in thehydrophilic polymer to the total molar content of the oxygen containinggroups in an active can be calculated as shown below:

$\left( \frac{\begin{matrix}{{Total}\mspace{14mu} {Oxyl}\mspace{14mu} {moles}\mspace{14mu} {for}\mspace{14mu} a\mspace{14mu} {given}\mspace{14mu} {weight}} \\{{of}\mspace{14mu} {polymer}\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {dosage}\mspace{14mu} {form}}\end{matrix}}{\begin{matrix}{{Total}\mspace{14mu} {molar}\mspace{14mu} {oxygen}\mspace{14mu} {containing}\mspace{14mu} {groups}} \\{{in}\mspace{14mu} {Active}\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {dosage}\mspace{14mu} {form}}\end{matrix}} \right)$

As used herein, “solid dosage form” of the present invention refers tothe unitary dispensable solid dosage comprising a pre-determined amountof the actives in the composition of the invention wherein the dosageform is intended to deliver one therapeutic dose per administration.Examples of known solid dosage forms include without limitation,tablets, capsules, caplets, mini tablets, powders, pellets, granules,triturates, solid solutions etc. In one embodiment the tablet, minitablet, powder, pellets, and granules may be coated with a suitable aconventional coating material to achieve, for example, greatershelf-life stability (photo-stability, chemical stability,moisture-stability etc), or to enhance identification (color coating) orto enhance the organoleptic perceptions (include flavor and/orsweetener, prevent bad taste and/or odor, etc.). Tablets and caplets maybe scored to facilitate division of dosing. The capsules containingpowder, pellets or granules or tablets or mini tablets can be alsocoated. In a specific embodiment, the tablet is a matrix tablet wherein,the two or more actives of the invention can be present as a homogenousadmixture within a matrix and presented as a monolithic tablet.

The term “guaifenesin” refers to the expectorant compound(3-(2-methoxyphenoxy)-1,2-propanediol). For the purpose of the currentinvention, guaifenesin can be used in the form of a 100% pure powder oras a pre-granulate form (for example, for direct compression process) orits equivalent form. It should also be noted that a mixture of the saidguaifenesin forms can be used.

The term “codeine” refers to the narcotic as classified under scheduleII of DEA controlled substances and refers to the compound itself aswell as its pharmaceutically acceptable salts, hydrates, polymorphs,solvates, isomers and the like. Non-limiting examples ofpharmaceutically acceptable codeine salts include, but are not limitedto, codeine phosphate, codeine hydrochloride, codeine phosphate, codeinesulfate, codeine citrate, and combinations thereof. In one embodimentcodeine is in the form of codeine, codeine sulphate, codeine phosphateor combinations thereof. In a specific embodiment, codeine is in theform of codeine sulphate, or codeine phosphate or combinations thereof.

The term “hydrocodone” refers to the narcotic as classified underSchedule II of DEA controlled substances and refers to the compounditself as well as its pharmaceutically acceptable salts, hydrates,polymorphs, solvates, isomers and the like. Non-limiting examples ofpharmaceutically acceptable hydrocodone salts include, but are notlimited to, hydrocodone bitartrate, and combinations thereof.

The term “substantially free” of a particular component or compound,such as “substantially free of ionic polymer” should be understood asmeaning less than 5 wt %, or less than 3 wt % of less than 2 wt % of thetotal composition. In another aspect, substantially free can refer toless than 1 wt % of the designated component. For example, a compositionthat is said to be substantially free of ionic polymer can have lessthan 5 wt %, or less than 3 wt %, or less than 2 wt %, or less than 1 wt% of the ionic polymer. In some embodiments, the compositions and oraldosage forms of the present invention can be free of ionic polymer.

As used herein, the terms “release” and “release rate” are usedinterchangeably to refer to the discharge or liberation of a substance,including without limitation a drug, from a dosage form into asurrounding environment such as an aqueous medium either in vitro or invivo.

As used herein, the term “immediate release” refers to the release ofactive from a dosage form, wherein, T_(25%) release is less than 0.3hour, T_(50%) release is less than 0.5 hour and T_(75%) release is lessthan 0.7 hour and wherein the release of dosage form is determined usinga USP Type II (paddle) Dissolution Apparatus set at 50 rpm in about 900mL of 0.1N hydrochloric acid solution in water at about 37° C. Theimmediate release dosages (for example, in the form of tablet) are usedherein to compare with the dosage forms of the current invention. Theimmediate release dosage form can comprise a single active or acombination of actives that are being compared. In one aspect, thedosage forms of the current invention does not contain any of theactives as an immediate release layer or component or portion, orfraction, nor is a combination of immediate release and sustainedrelease components.

The terms “release rate controlling agent”, “release modifying agent”,“release modulating agent”, and “release modifiers” are usedinterchangeably and refer to pharmaceutically acceptable agents ordevices that are able to alter, delay, target, increase or decrease, orotherwise customize, the release rates of at least one of the contentsof the dosage form, when exposed to an aqueous use environment. In oneembodiment, the release rate controlling agent is a non-ionicoxyl-containing hydrophilic polymer.

As referred to herein, resistance to “alcohol extraction” or “alcoholassociated dose dumping” in presence of alcohol can be tested for thedosage forms of this invention, by subjecting the dosage form toSimulated Gastric Fluid (SGF) with 20% ethanol. A typical manner inorder to obtain 900 ml of Simulated Gastric Fluid (SGF) with 20% ethanolis by mixing 800 ml of SGF with 210 ml of 95% ethanol/water (whichprovides 200 ml ethanol) and taking 900 ml of the mixture. Resistance toalcohol extraction can also be tested using an aqueous solutioncomprising 40% ethanol and performing a drug release testing in presenceof alcohol, the results can be compared to the release of drug from thesame release medium without alcohol added.

Unless otherwise specified, a drug release rate obtained at a specifiedtime refers to the in vitro drug release rate obtained at the specifiedtime following implementation of an appropriate release testing. Themean time at which a specified percentage of the drug within a dosageform has been released to the medium of test may be referenced as the“T_(x %)” value, where “x” is the percent of drug that has beenreleased. For example, the commonly used reference measurement forevaluating drug release from dosage forms is the time at which 25%, 50%and/or 75% of drug within the dosage form has been released. Thismeasurement is referred to as the “T_(25%)”, “T_(50%)”, “T_(75%)” forthe dosage form.

As used herein, “subject” refers to a mammal that may benefit from theadministration of a drug composition or method of this invention.Examples of subjects include humans, and may also include other animalssuch as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals.In one embodiment, the subject is a human subject.

The term “oral administration” represents any method of administrationin which an active agent can be administered by swallowing, chewing, orsucking of the dosage form. In an embodiment, the pharmaceutical tabletof this invention is swallowed whole with the aid of a liquid such aswater, milk, juice and the like.

For the purpose of this invention, unless otherwise stated,administration to a subject under fed condition (“fed treatment”) refersto administration such that following an overnight fast of at least 10hours, the subject starts the test meal 30 minutes prior toadministration of the dosage form. The dosage form is administered 30minutes after start of the test meal, wherein the dosage form isadministered with about 240 mL of water. No food is allowed for at least4 hours post-dose. Water can be allowed as desired except for one hourbefore and after drug administration.

Similarly, unless specifically mentioned, administration to subjectsunder fasted condition (“fasted treatment”) refers to administrationsuch that following an overnight fast of at least 10 hours, the dosageform is administered with about 240 mL of water to the subject. No foodis allowed for at least 4 hours post-dose. Water can be allowed asdesired except for one hour before and after drug administration. A“test meal” for evaluating food-effect refers to a high-fat(approximately 50 percent of total caloric content of the meal) andhigh-calorie (approximately 800 to 1000 calories) meal. The test mealshould derive approximately 150, 250, and 500-600 calories from protein,carbohydrate and fat, respectively.

As used herein, “no food effect”, “refractory to food intake”, “absenceof food effect” and the like refer to the property such of an oraldosage form such that following single dose administration of an oraldosage form to a subject under either fed or fasted conditions, thevariation in the pharmacokinetic parameters for the active agents in theoral dosage form is not more than about 40% as compared to the samepharmacokinetic parameter measured in the same subject when the oraldosage form is administered under the opposite condition (i.e. fed vs.fasted). In one embodiment, the pharmacokinetic parameters, particularlythe plasma mean C_(max) or the mean AUC_(0-inf) or both, for therespective actives does not vary by more than about 30% whenadministered under a fed versus a fasted condition.

As used herein, “steady state” or “C_(ss)” refers to the concentrationof an active in a body fluid (usually plasma) when the rates of drugadministration and drug elimination are equal. C_(ss) is a valueapproached as a limit and is achieved, theoretically, following the lastof an infinite number of equal doses given at equal intervals. C_(ss)max) is the maximum value under steady state conditions and C_(ss) minis the minimum value achieved under steady state conditions.

As used herein, an “effective amount” or a “therapeutically effectiveamount” of a drug refers to a non-toxic, but sufficient amount of thedrug, to achieve therapeutic results in treating a condition for whichthe drug is known to be effective. It is understood that variousbiological factors may affect the ability of a substance to perform itsintended task. Therefore, an “effective amount” or a “therapeuticallyeffective amount” may be dependent in some instances on such biologicalfactors. Further, while the achievement of therapeutic effects may bemeasured by a physician or other qualified medical personnel usingevaluations known in the art, it is recognized that individual variationand response to treatments may make the achievement of therapeuticeffects a somewhat subjective decision. The determination of aneffective amount is well within the ordinary skill in the art ofpharmaceutical sciences and medicine. See, for example, Meiner andTonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographsin Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein byreference.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint. As used herein, aplurality of items, structural elements, compositional elements, and/ormaterials may be presented in a common list for convenience. However,these lists should be construed as though each member of the list isindividually identified as a separate and unique member. Thus, noindividual member of such list should be construed as a de factoequivalent of any other member of the same list solely based on theirpresentation in a common group without indications to the contrary.

As used herein, a plurality of items, structural elements, compositionalelements, and/or materials may be presented in a common list forconvenience. However, these lists should be construed as though eachmember of the list is individually identified as a separate and uniquemember. Thus, no individual member of such list should be construed as ade facto equivalent of any other member of the same list solely based ontheir presentation in a common group without indications to thecontrary.

Concentrations, amounts, levels and other numerical data may beexpressed or presented herein in a range format. It is to be understoodthat such a range format is used merely for convenience and brevity andthus should be interpreted flexibly to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges or decimalunits encompassed within that range as if each numerical value andsub-range is explicitly recited. As an illustration, a numerical rangeof “about 1 to about 5” should be interpreted to include not only theexplicitly recited values of about 1 to about 5, but also includeindividual values and sub-ranges within the indicated range. Thus,included in this numerical range are individual values such as 2, 3, and4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as wellas 1, 2, 3, 4, and 5, individually. This same principle applies toranges reciting only one numerical value as a minimum or a maximum.Furthermore, such an interpretation should apply regardless of thebreadth of the range or the characteristics being described.

Reference will now be made in detail to preferred embodiments of theinvention. While the invention will be described in conjunction with thepreferred embodiments, it will be understood that it is not intended tolimit the invention to those preferred embodiments. To the contrary, itis intended to cover alternatives, variants, modifications, andequivalents as may be included within the spirit and scope of theinvention as defined by the appended claims.

With this in mind, the present invention provides for pharmaceuticaltablets for delivering at least two actives, at least one of which is atri-oxy active agent. In one embodiment, a pharmaceutical tablet fororal administration once every 12 hours is provided. The tablet includesa first active agent that is a tri-oxy active agent, a second activeagent, and a release rate controlling non-ionic oxyl-containinghydrophilic polymer. The total oxyl content of the hydrophilic polymerin the tablet is from about 4×10⁻⁴ moles to about 2.0×10⁻³ moles. Thetablet is a matrix tablet and a single-dose administration of one ormore tablets to a subject under fasted conditions provides a meanC_(max) for each of the first active agent and the second active agentthat is 70% to 135% of a respective mean C_(max) provided byadministering an immediate release oral dosage to a subject under fastedconditions every 4 to 6 hours over a 12 hour time period, whereincumulative dosage amounts administered over the 12 hour time period ofeach active agent in the immediate release oral dosage is equivalent tothe respective amount of each active agent in the pharmaceutical tablet.

In another embodiment, a pharmaceutical tablet for oral administrationonce every 12 hours is provided. The tablet includes a first activeagent that is a tri-oxy active agent, a second active agent, and arelease rate controlling non-ionic oxyl-containing hydrophilic polymer.The total oxyl content of the hydrophilic polymer in the tablet is fromabout 4×10⁻⁴ moles to about 2.0×10⁻³ moles. The tablet is a matrixtablet and a single-dose administration of one or more tablets to asubject under fed conditions provides a mean C_(max) for each of thefirst active agent and the second active agent that is 70% to 135% of arespective mean C_(max) provided by administering an immediate releaseoral dosage to a subject under fed conditions every 4 to 6 hours over a12 hour time period, wherein cumulative dosage amounts administered overthe 12 hour time period of each active agent in the immediate releaseoral dosage is equivalent to the respective amount of each active agentin the pharmaceutical tablet.

In another embodiment, a pharmaceutical tablet for oral administrationonce every 12 hours is provided. The tablet includes a first activeagent that is a tri-oxy active agent, a second active agent, and arelease rate controlling non-ionic oxyl-containing hydrophilic polymer.The total oxyl content of the hydrophilic polymer in the tablet is fromabout 4×10⁻⁴ moles to about 2.0×10⁻³ moles. The tablet is a matrixtablet and a single-dose administration of one or more tablets to asubject under fasted conditions every twelve hours provides a meanC_(max) for each of the first active agent and the second active agentthat is 70% to 135% of a respective mean C_(max) provided byadministering the same oral dosage to the subject under fed conditionsevery 12 hours. The same amount of each active agent is administeredover any given 12 hour period.

In another embodiment, a pharmaceutical tablet for dosing once every 12hours is provided. The tablet is a matrix tablet and includes a firstactive agent that is a tri-oxy active agent, a second active agent, anda release rate controlling non-ionic oxyl-containing hydrophilicpolymer. The tablet is formulated such that when placed in a USP Type 2dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acidsolution in water at 37° C., about 50 wt % of the first active agent isreleased in about 1.5 hours to about 3.8 hours. The ratio of the amountof first active released from the tablet to the amount of second activeagent released at 1 hour and at 4 hours is between about 0.7:1 and about1.3:1. In one embodiment, the tablets of the present invention can besingle layer tablets. In other words, the active agents are present in acommon tablet matrix and not separated into distinct active agentlayers.

In yet a further embodiment, the present invention provides for a methodof treating cough and/or cold symptoms in a human subject, comprisingadministering to the human subject a pharmaceutical tablet in accordancewith one of the embodiments of the present invention. In yet anotherembodiment, a method of minimizing sleep disturbance for a human subjecthaving cough and/or cold symptoms is provided in which the methodcomprises administering to the human subject a pharmaceutical tablet inaccordance with an embodiment of the present invention. In one aspect,the methods of the present invention can be accomplished without regardto food consumption. In one embodiment, the mean C_(max) of the firstactive agent will vary not more than 40% when administered with food ascompared to administration of the same tablet to the same subjectwithout food.

The oral dosage forms disclosed herein can be, but do not have to be,administered with food (or meals). In one embodiment, the composition ororal dosage capsule can be administered with a meal, such as a meal thatprovides about 200 to about 1000 calories of energy. In anotherembodiment, the oral dosage form can be administered with a standardmeal. In another embodiment, the oral dosage form can be administeredwith a meal has no fat, low fat, medium fat or high fat. Thecompositional make-up of the meals that are administered can varydepending on the tastes and dietary needs of a subject.

The oral dosage forms (e.g. tablets) disclosed herein can be orallyadministered in a 12 hours' dosing regimen or as “12 hour dosing” thatis suitable to the needs of the subject. The dosage form is alsoreferred to as or “12 hour dosage form”, or “12 hour product”. The 12hours' dosing regimen can include administering the dosage forms in themorning, in the evening, at about night time or combinations thereof.The 12 hours' dosing regimen can include dosing one or more dosage unitsat one or more administration times. In one embodiment, thepharmaceutical dosage forms of the current invention can be administeredonce every 12 hours. Further, the pharmaceutical dosage forms of thecurrent invention can be administered twice in a day (or about 24 hours)usually about 12 hours apart. In another embodiment, the pharmaceuticaldosage form of the current invention is administered once every 12 hoursas a single oral dosage tablet.

In one embodiment, the 12 hour oral dosage forms of the invention has nofood-effect wherein, the dosage form provides upon a single doseadministration to a subject under fed and fasted conditions, a ratios ofthe corresponding mean C_(max) or AUC_(0-inf), or both, for therespective actives between fed and fasted treatments, in the rangebetween about 0.7 and about 1.3. In another specific embodiment, the 12hour oral dosage forms of the invention provides upon a single doseadministration to a subject under fed and fasted conditions, a ratio ofthe mean AUC_(0-inf) or AUC_(0-t) or both, for the respective activebetween fed and fasted treatments, in the range between 0.7 and 1.3.

The pharmaceutical tablets of the present invention include a firstactive agent, which is a tri-oxy active agent. In one embodiment, thefirst active agent can be codeine or its pharmaceutically acceptablesalts. In another embodiment, the first active agent can be guaifenesin.It yet another embodiment, the first active agent can be hydrocodone orits pharmaceutically acceptable salts.

The pharmaceutical tablets of the present invention include a secondactive agent, wherein, the second active agent can, but does not needto, be a tri-oxy active. Thus, in some embodiments the tablet caninclude a first and a second active agent that that are each tri-oxyactive agents, while in other embodiments the second active agent can bea non-tri-oxy active agent. Non-limiting examples of non-tri-oxy secondactive agents that can be used in the tablets can includechlorpheniramine, cyclopentamine, dexchlorpheniramine, diphenhydramine,brompheniramine, dexbrompheniramine, dextromethorphan tripolidine,desloratadine, cyproheptadine, phenylephrine, pyrallamine,pseudoephedrine, azalastin, loratidine, theophylline, their salts oresters thereof, and combinations thereof. In one embodiment, the secondactive agent is a non-tri-oxy active agent. In another embodiment, thesecond active agent is chlorpheniramine or its pharmaceuticallyacceptable salt. Exemplary embodiments of first and second active agentcombinations include, but are not limited to, codeine and guaifenesin,codeine and chlorpheniramine, guaifenesin and hydrocodone, guaifenesinand chlorpheniramine, and hydrocodone and chlorpheniramine, codeine andpseudoephedrine, guaifenesin and pseudoephedrine, guaifenesin anddextromethorphan, codeine and dextromethorphan, hydrocodone andchlorpheniramine; hydrocodone, chlorpheniramine and pseudoephedrine orphenylephrine.

The pharmaceutical tablets of the present invention also include anon-ionic oxyl-containing hydrophilic polymer. In one embodiment, thenon-ionic hydrophilic polymer is a release-rate controlling polymer. Insome embodiments, the tablets are also free, or substantially free, ofionic polymers. Non-limiting examples of non-ionic release-ratecontrolling hydrophilic polymers that can be used include cellulosepolymers such as hydroxypropyl cellulose, methyl cellulose,carboxymethyl cellulose, hydroxypropyl methyl cellulose, combinationsthereof, and the like.

In one embodiment, the hydrophilic polymer is a cellulose polymer. Inanother embodiment, the hydrophilic polymer is a hydroxypropyl methylcellulose. In a specific embodiment, the polymer has an average methoxycontent of about 15 mole % to about 30 mole %. In another specificembodiment, the polymer has an average methoxy content of about 18 mole% to about 25 mole %. In another embodiment, when used in a tabletdosage form of the invention, the total oxyl content of the hydrophilicpolymer in the tablet is from about 4×10⁻⁴ moles to about 2.0×10⁻³moles. In further embodiment, when used in a tablet dosage form of theinvention, the hydrophilic polymer provides a methoxy content of about2.2×10⁻⁴ to 1.2×10⁻³ moles per tablet. It should be noted that a mixtureof the said hydroxypropyl methyl celluloses can be used wherein therequisite range of methoxyl content per dosage form (example, tablet) isobtained.

In still further embodiments, when the cellulose polymer ishydroxypropyl methyl cellulose, it can be present in the tablet in anamount of about 40 mg to about 175 mg, or in an amount of about 60 mg toabout 150 mg, or in an amount of about 60 mg to about 125 mg. In aspecific embodiment, the hydroxypropyl methyl cellulose can have anaverage apparent viscosity of about 3000 cP to about 15000 cP whendetermined on a 2% solution in water at 20° C. In another embodiment,the hydroxypropyl methyl cellulose can have an average apparentviscosity of about 3000 cP to about 5000 cP when determined on a 2%solution in water at 20° C. It should be noted that a mixture ofhydroxypropyl methyl celluloses can be used to achieve a desiredviscosity within the above defined ranges.

Without being limited by theory, it is believed that there exists aninteraction at the molecular level between the oxyl-content of thenon-ionic hydrophilic cellulose polymer and the oxygen-containing groupsin the tri-oxy actives of the invention. It is believed that thisinteraction influences the rate and extent of hydration, gelation and/orerosion of the polymer which in turn enables the requisite performancefor a matrix tablet formulated for administration once every twelvehours. Therefore, a particular range of the amount of the non-ionicpolymer in a tri-oxy active combination solid dosage form (e.g. matrixtablet) can provide a release profile which enables 12 hour dosing.Accordingly, Applicants have discovered that a total oxyl content of4×10⁻⁴ moles to about 2.0×10⁻³ moles from the polymer per dosage form(e.g. tablet) enables a 12 hour dosing therapy of at least one tri-oxyactive in combination with another active of the invention. Applicantsfurther believe that one or more of the oxygen containing groups in thetri-oxy active is responsible for the synergistic effect with theoxyl-containing polymer. Furthermore, the levels of the oxyl-containingpolymer enabling a 12 hour solid dosage form is specific to an activethat contains at least three oxygen-containing groups; preferably atleast one of each of methoxyl group and ether groups and at least one ofcarbonyl or hydroxyl groups. In contrast, as seen through some of theexperimental examples disclosed herein, a higher or lower methoxycontent of the polymer can result in an undesirably fast or very slowrelease of the actives from the dosage form thereby failing to complywith the typical requirements for the 12 hour dosing regimen.

The pharmaceutical tablets of the present invention can be formulatedsuch that upon single-dose administration of one or more tablets to asubject under fasted conditions, the tablets can provide a meanAUC_(inf) of each of the first active agent and the second active agentthat is 70% to 135% of a respective mean AUC_(inf) provided byadministering an immediate release oral dosage to a subject under fastedconditions every 4 to 6 hours over a 12 hour time period. The cumulativedosage amounts administered over the 12 hour time period of each activeagent in the immediate release oral dosage is equivalent to therespective amount of each active agent in the pharmaceutical tablet.Similarly, the tablets can be formulated such that upon single-doseadministration of one or more tablets to a subject under fastedconditions provides a mean AUC₀₋₁₂ of each of the first active agent andthe second active agent that is 70% to 135% of a respective mean AUC₀₋₁₂provided by administering an immediate release oral dosage to a subjectunder fasted conditions every 4 to 6 hours over a 12 hour time period.As above, the cumulative dosage amounts administered over the 12 hourtime period of each active agent in the immediate release oral dosage isequivalent to the respective amount of each active agent in thepharmaceutical tablet.

In one embodiment, the first active agent is codeine or itspharmaceutically acceptable salt. In one embodiment, the codeine can beresin free or substantially resin free. The codeine can comprise about35 wt % or less, of the total tablet weight. The codeine can comprisefrom about 20 wt % to about 35 wt % of the total tablet weight. Inanother embodiment, the codeine can comprise about 25 wt % to about 30wt % of the total tablet weight. In another embodiment, the codeine cancomprise about 3 wt % to about 5 wt % of the total tablet weight. In afurther embodiment, the codeine can comprise about 3.5 wt % to about 4wt % of the total tablet weight. In another embodiment, when the firstactive agent is codeine, the ratio of total content of the oxyl groupsin the hydrophilic polymer to the total molar content of theoxygen-containing groups in the codeine is from about 2.5 to about 9. Inanother embodiment, when the first active agent is codeine, the ratio oftotal content of the oxyl groups in the hydrophilic polymer to the totalmolar content of the oxygen-containing groups in the codeine is fromabout 2.5 to about 4.5.

In a further embodiment, the tablet can have a first active agent ofcodeine or its pharmaceutically acceptable salts and the second activeagent can be chlorpheniramine or a pharmaceutically acceptable saltthereof. The codeine and chlorpheniramine tablet can, upon single-doseadministration to a subject under fasted conditions, provide a meanT_(max) for codeine of about 2.2 hours to about 3.4 hours and a meanT_(max) for chlorpheniramine of about 5 hours about 14 hours. In anotheraspect, the codeine and chlorpheniramine tablet can, when placed in aUSP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 Nhydrochloric acid solution in water at 37° C., provide a release of theactive agents such that about 30% to about 40% of the amount of codeineis released in the first 0.5 to 1 hour, and the amount ofchlorpheniramine released in the same time is between 80% and 120% ofthe amount of codeine released. In another aspect, when placed in a USPType 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloricacid solution in water at 37° C., the time to release about 50 wt % ofthe codeine and chlorpheniramine is about 1.5 to about 3 hrs. In anotheraspect, when placed in a USP Type 2 dissolution apparatus at 50 rpm in900 mL of 0.1 N hydrochloric acid solution in water at 37° C., the timeto release about 50 wt % of the codeine and chlorpheniramine is about1.6 to about 2.4 hrs. In yet a further embodiment, the tablet canprovide a release of about 45-60% of the amount of codeine and about45-60% of the amount of chlorpheniramine in about 2 hours. In yet afurther aspect, when placed in a USP Type 2 dissolution apparatus at 50rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C.,the tablet can provide a release of the active agents such that at leastabout 70% of the amount of chlorpheniramine is released in about 3 hoursto 4 hours, and the amount of codeine released in the same time periodis between 80% and 120% of the amount of chlorpheniramine released. Instill a further embodiment, the pharmaceutical tablet can be formulatedsuch that when placed in a USP Type 2 dissolution apparatus at 50 rpm in900 mL of 0.1 N hydrochloric acid solution in water at 37° C., the ratioof the amount of first active released to the amount of second activeagent released at a single time point between 1 hour and 4 hours isabout 0.8:1 and about 1.2:1.

In one embodiment, the dosage forms of the current invention can includea third active agent. The third active agent can be a tri-oxy activeagent or a non-tri-oxy active agent. In one embodiment, the active agentcan be a decongestant. In one embodiment, the decongestant can bepseudoephedrine, phenylephrine, and their pharmaceutically acceptablesalts. Example combinations of first, second, and third active agentsthat can be combined in the pharmaceutical tablets of the presentinvention include, without limitation, 1) codeine, chlorpheniramine, andpseudoephedrine; 2) codeine, chlorpheniramine, and phenylephrine; 3)codeine, guaifenesin, and pseudoephedrine; 4) codeine, guaifenesin, andphenylephrine; 5) guaifenesin, hydrocodone, and pseudoephedrine; 6)guaifenesin, hydrocodone, and phenylephrine; and the like.

In one aspect, a single-dose administration of one or more tablets to asubject under fasted conditions can provide a mean C_(max) for each ofthe first active agent, second active agent and the third active agentthat is about 70% to about 135% of a respective mean C_(max) provided byadministering an immediate release oral dosage, as a combination orrespective single active dosage form, to a subject under fastedconditions every 4 to 6 hours over a 12 hour time period, whereincumulative dosage amounts administered over the 12 hour time period ofeach active agent from the immediate release dosage forms are equivalentto the respective amount of each active agent in the pharmaceuticaltablet. In one aspect, the pharmaceutical matrix tablet of the currentinvention, with the three actives, when placed in a USP Type 2dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acidsolution in water at 37° C., where in the amount of second and thirdactive released is within 70% to 135% of release of first active whenmeasured between about 1 and 4 hours.

In a further embodiment, the first active agent is codeine and thesecond active agent is guaifenesin. It is noteworthy that because boththe codeine and the guaifenesin are tri-oxy active agents and either ofthem could be considered as the first active agent. The codeine can bepresent in the amounts discussed above, and the guaifenesin can bepresent in amounts of about 600 mg/tablet to about 1200 mg/tablet. Inanother embodiment, the guaifenesin can be present in an amount of 600mg/tablet. In one embodiment, the codeine can be present in an amount ofabout 30 mg, the guaifenesin can be present in an amount of about 600mg, and the hydrophilic polymer can be hydroxypropyl methyl celluloseand comprises about 8 wt % to about 20 wt % of the tablet. In a stillfurther specific embodiment, the hydrophilic polymer can behydroxypropyl methyl cellulose and comprises about 8 wt % to about 15 wt% of the tablet.

In another embodiment, the pharmaceutical tablet includes codeine andguaifenesin and upon administration to a subject under fasted conditionsthe tablet provides a guaifenesin C_(min) of about 3 ng/mL or more, atsteady state. In another embodiment, the tablet provides at steadystate, a guaifenesin mean C_(max) of about 850 ng/mL to about 1700ng/mL, and a codeine mean C_(max) of about 30 ng/mL to about 90 ng/mL.

In one aspect, when placed in a USP Type 2 dissolution apparatus at 50rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C.,the T_(25%) for both codeine and the guaifenesin is about 0.5-1 hour andthe T_(75%) for both the codeine and the guaifenesin is about 5 hours.In another aspect, when the tablet is placed in a USP Type 2 dissolutionapparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution inwater at 37° C., about 25% to about 35% of the amount of guaifenesin isreleased in the 0.5-1 hour, and the amount of codeine released in thesame time is between 70% and 130% of the amount of guaifenesin released.In another aspect, when the tablet is placed in a USP Type 2 dissolutionapparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution inwater at 37° C., about 50 wt % of each of the guaifenesin and thecodeine are released in about 1.5 to about 3 hours. In anotherembodiment, when the tablet is placed in a USP Type 2 dissolutionapparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution inwater at 37° C., about 50 wt % of each of the guaifenesin and thecodeine are released in about 1.6-2.4 hours. In still a further aspect,when the tablet is placed in a USP Type 2 dissolution apparatus at 50rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., atleast about 80% of the amount of codeine is released in about 8 hours,and the amount of guaifenesin released in the same time period isbetween 80% and 120% of the amount of codeine released. In oneembodiment, the when the active agents are codeine and guaifenesin andthe dissolution is accomplished according to the methodologies describedabove, the ratio of the amount of first active released to the amount ofsecond active agent released at a single time point between 1.5 hoursand 4 hours is about. 0.7:1 and about 1.3:1.

In a further embodiment, the first active agent can be guaifenesin. Theguaifenesin can be present in amounts of about 600 mg/tablet to about1200 mg/tablet. In one embodiment, the guaifenesin can be present in anamount of 600 mg/tablet. In one embodiment, the ratio of the total molarcontent of oxyl groups in the hydrophilic polymer to the total molarcontent of the oxygen containing groups in the guaifenesin can be about0.07 to 0.18. When guaifenesin is the first active agent, the secondactive agent can be hydrocodone. Like guaifenesin, hydrocodone is atri-oxy active agent and thus either of them could be considered to bethe first active agent in a tablet having both guaifenesin andhydrocodone. In the guaifenesin-hydrocodone combination tablet, in oneembodiment the tablet can be such that upon administration to a subjectthe tablet can provide a guaifenesin C_(min) of about 3 ng/mL or more,at steady state. In one embodiment, the tablet can be such that theguaifenesin can be present in an amount of about 600 mg to about 1200mg, the hydrocodone can be present in an amount of 5 mg to 10 mg, andthe hydrophilic polymer can be hydroxypropyl methyl cellulose and can bepresent in an amount of 55 mg to about 165 mg.

In still a further embodiment, the tablet can be such that theguaifenesin can be present in an amount of about 600 mg/tablet, thehydrocodone can be present in an amount of 5 mg/tablet, and thehydrophilic polymer can be hydroxypropyl methyl cellulose and comprisesabout 8 wt % to about 20 wt % of the tablet. In another specificembodiment, the hydrophilic polymer can be hydroxypropyl methylcellulose and comprises about 8 wt % to about 15 wt % of the tablet. Inanother embodiment, the tablet provides at steady state, a guaifenesinmean C_(max) of about 850 ng/mL to 1700 ng/mL, and a hydrocodone meanC_(max) of about 12 ng/mL to 25 ng/mL.

When the pharmaceutical tablets include guaifenesin and hydrocodone asthe first and second active agents respectively, the tablet can beformulated such that when placed in a USP Type 2 dissolution apparatusat 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37°C., the T_(25%) for both guaifenesin and the hydrocodone is from about25 minutes to about 75 minutes and the T_(75%) for both the guaifenesinand the hydrocodone is from about 3 hours to about 7 hours. In anotherembodiment, the tablet can be formulated such that when placed in a USPType 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloricacid solution in water at 37° C., about 35% or less of the amount ofguaifenesin and about 20% to 40% of the amount of the hydrocodone arereleased in 0.5-1 hour. In yet a further embodiment, the tablet can beformulated such that when placed in a USP Type 2 dissolution apparatusat 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37°C., about 40-65% of the amount of guaifenesin and about 40-65% of theamount of hydrocodone are released in about 2 hours. In anotherembodiment, the tablet can be formulated such that wherein when placedin a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 Nhydrochloric acid solution in water at 37° C., the time to release about50% of the amount of guaifenesin and of hydrocodone is about 2 hours.

In another embodiment, the tablet can be formulated such that whenplaced in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1N hydrochloric acid solution in water at 37° C., about 35% or less ofthe amount of guaifenesin and about 20-40% the amount of guaifenesin isreleased in the first 0.5-1 hour, and the amount of hydrocodone releasedin the same time is between 70% and 130% of the amount of guaifenesinreleased.

In still a further embodiment the tablet can be formulated such thatwhen placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of0.1 N hydrochloric acid solution in water at 37° C., at least about 80%of the amount of hydrocodone is released in about 8 hours, and theamount of guaifenesin released in the same time period is between 80%and 120% of the amount of hydrocodone released. In yet anotherembodiment, when the active agents are guaifenesin and hydrocodone andthe release of the actives is determined according to the methodologiesdescribed above, the ratio of the amount of first active released to theamount of second active agent released at a single time point between1.5 hours and 4 hours is about 0.7:1 and about 1.3:1.

In still a further embodiment the tablet can be formulated such thatwhen placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of0.1 N hydrochloric acid solution in water at 37° C., at least about 80%of the amount of hydrocodone is released in about 8 hours, and theamount of guaifenesin released in the same time period is between 80%and 120% of the amount of guaifenesin released.

In some embodiments, the first active agent can be hydrocodone or itspharmaceutically active salts. The hydrocodone can comprise 0.5 wt % toabout 1 wt % of the tablets and can be present in amounts of about 5mg/tablet to about 10 mg/tablet. In embodiments where hydrocodone is thefirst active agent the non-ionic hydrophilic polymer can behydroxypropyl methyl cellulose and can be present in amounts of 40mg/tablet to about 175 mg/tablet.

In another aspect, the matrix tablet of the current invention can beformulated such that it does not exhibit “dose dumping” effect whentested in vitro in a USP Type 2 dissolution apparatus at 50 rpm in 900mL of 0.1 N hydrochloric acid solution in water containing from about4%-40% v/v of ethanol, at 37° C. Accordingly, in one embodiment, thetablet does not release the entire amount of the tri-oxy active in about2 hours or less. In another embodiment, the amount of the tri-oxy activereleased from the tablet under the said in vitro “dose dumping” releasetesting conditions is about 180% or less, preferably, about 150% or lessor even more preferably 130% or less of the amount of the respectivetri-oxy active released in about 2 hours in a 900 mL 0.1 N hydrochloricacid solution in water but without ethanol, at 37° C., taken in a USPType 2 dissolution apparatus at 50 rpm.

The compositions and the solid oral dosage forms (example, tablets) ofthe current invention can also include one or more of the pharmaceuticalprocess aids selected from the group known in the art, consisting ofbinders, bufferants, compacting aids, diluents, disintegrants, flavors,colorants, taste-masking agents, pH modifiers, lubricants, glidants,thickening agent, opacifying agent, humectants, desiccants, effervescingagents, sweeteners, plasticizing agents, wetting agents and the like.The amount of each of these excipients per dosage form (example, matrixtablet) can vary depending on the amount of the actives and non-ionicoxyl-containing hydrophilic polymer in the dosage form. For example, thetabletting aids are added in amounts typically known to one of relevantskill in the art. Non-limiting examples of the tabletting aids suitablefor use in the pharmaceutical tablets of the present invention includenon-crystalline cellulose; microcrystalline cellulose; dextrose;croscarmellose; cyclodextrins; β-cyclodextrins; α-cyclodextrin;dextrates; sorbitol; lactose; sucrose; maltose; galactose;polyvinylpyrrolidone (povidone K 12 to K120); crospovidone; polyvinylalcohol; glycerol; glucose; polyols such as mannitol; xylitol orsorbitol or their combinations; polyethylene glycol esters; alginates;sodium alginate; poly(lactide coglycolide); gelatin; crosslinkedgelatin; agar-agar; sodium dodecyl sulfate; glycerin; polyethyleneglycols of mol wt range from about 100 to about 20,000 or theirmixtures; lactose; guar gum; xanthan gum; starches; gum arabic;dextrins; dibasic calcium phosphate; cyclodextrins or its derivativesand their combinations; sodium starch glycolate; croscarmellose sodium;galactomannan; tricalcium phosphate; maltodextrin or its derivatives andtheir combinations; polyoxyethylene stearate; carnuaba wax; fattyalcohols; sugar esters; sugar ethers; shellacs; tocopherol; tocopherolpolyethyleneglycol succinate; tocopherol succinate; tocopherol acetate;talc, magnesium stearate, stearic acid, sodium lauryl sulphate, and thelike.

The solid oral dosage forms the present invention can be manufactured astablet or capsule dosage forms either by dry blending/granulationmethods, or by wet granulation methods. For example, the actives can becombined with one or more pharmaceutically acceptable excipients/aidsdescribed above and blended to get a homogenous mixture which can becompressed into a tablet or into mini tablets to be disposed into acapsule. In another embodiment, the homogenous mixture can be kneadedwith a binder solution to get a wet granulate mass which can be driedand sized, for example by passing through ASTM mesh #30. The resultinggranules can be optionally blended with pharmaceutical aids such asdiluents, lubricants, disintegrants etc, and disposed into capsules orcompressed into tablets. In another particular case, the tablets can becoated. Non-limiting examples of the processes that can be used toprepare the compositions and dosage forms of this invention includemixing melting, prilling, size reduction, melt-spray congealing,co-precipitation, co-crystallization, encapsulation, co-milling, spry orfreeze drying, complexing, granulating, extruding, slugging, orcombinations thereof.

The solid oral dosage forms can also be formulated using melt-extrusionprocesses alone or in combination with other known processes. Forexample, in one embodiment, the required amounts of the actives andnon-ionic oxyl-containing hydrophilic polymer can be homogeneouslycombined with a sufficient amount of one or more pharmaceuticalexcipients/tableting aids prior to undergoing extrusion.

The dosage forms of the invention provide “no food effect” or the dosageform is “refractory to food intake”. Accordingly, in one embodiment, thepharmacokinetic parameters, particularly the plasma mean C_(max), andthe mean AUC_(0-inf) for the respective actives following a single doseadministration of the dosage form under fed or fasted conditions, doesnot vary by more than about 40%. In a preferred embodiment, thepharmacokinetic parameters, particularly the plasma mean C_(max), andthe mean AUC_(0-inf) for the respective actives does not vary by morethan about 30%. In another embodiment, the dosage forms of the inventionhas no food-effect and the dosage form provides, upon a single doseadministration to a subject under fed and fasted conditions, a ratio ofthe corresponding mean C_(max), or AUC_(0-inf), or both, for therespective actives between fed and fasted treatments, in the rangebetween about 0.7 and about 1.3. In still another embodiment, the dosageform of the current invention provides, upon a single doseadministration to a subject under fed and fasted conditions, a ratio ofthe mean AUC_(0-inf) or AUC_(0-t), or both, for the respective activebetween fed and fasted treatments, in the range between 0.7 and 1.3.

In another aspect, the present invention discloses pharmaceutical soliddosage form such as matrix tablet wherein, for a given dose levels oftwo actives, at least one of which is a tri-oxy active, an optimalnon-ionic oxyl-containing hydrophilic polymer level is tied to anoptimal Pk of each of both the actives, that is robust to differentialdose levels of the actives for 12 hour dosing.

EXAMPLES

The following examples are provided to promote a more clearunderstanding of certain embodiments of the present invention, and arein no way meant as a limitation thereon. Unless otherwise specified ormentioned, all the compositions provided in the examples are by measureof weight in the final composition.

Example 1 In Vitro Release Profiles of the Actives from Dosage Forms

The in vitro release profiles of the respective actives from the dosageform examples of the current invention were determined using a USP TypeII (paddle) Dissolution Apparatus set at 50 rpm in about 900 mL of 0.1Nhydrochloric acid solution in water at about 37° C. Aliquots sampledfrom the dissolution apparatus at pre-determined time intervals varyingfrom about 5 minutes up to about 36 hours were analyzed for therespective actives by employing an HPLC with a UV spectrophotometerdetector and using appropriate standard solutions. The amount of theactive released is then calculated from the concentrations of actives inthe medium and the volume of the medium, and expressed as a percentageof their amounts originally present in the dosage form.

Example 2 In Vivo Pharmacokinetic Evaluation of the Dosage Forms

Dosage forms of examples where indicated, were evaluated for in vivopharmacokinetic performance. The general study design was an open-label,randomized, single-dose, crossover performed on 10-12 volunteers. Ineach treatment period, subjects were housed from at least 12 hoursbefore dosing until after the 24-hour blood draw. There was at least5-day washout between treatment periods, during the study. The analysisof the plasma samples were carried out for the respective drugs usingLC-MS/MS.

The C_(max), T_(max), AUC_(0-t) and AUC_(0-∞) were calculated for thefirst and second actives in the plasma of the test subjects.Pharmacokinetic and statistical analyses were performed on the dataobtained from the subjects using Pharsight® WinNonlin®. Thepharmacokinetic parameters are defined as follows:

-   -   AUC_(0-t): The area under the plasma concentration vs. time        curve, from zero time to last measurable concentration of the        drug, as calculated by the linear trapezoidal method.    -   AUC (AUC_(0-∞)): The area under the plasma concentration versus        time curve from time 0 to infinity. AUC was calculated as the        sum of the AUC0-t plus the ratio of the last measurable plasma        concentration of the administered drug to the elimination rate        constant.    -   C_(max): The maximum measured plasma concentration of the        administered drug.    -   C₁₂: The plasma concentration of the administered drug 12 hours        post-dosing.    -   T_(max): The time at which the maximum measured plasma        concentration of the administered drug is achieved    -   C_(min): Minimum concentration of an active in the plasma        measured during steady state. It can be the minimum        concentration observed during the dosing period, in a        single-dose study.    -   Mean: Average value of measured parameter of all individual        subjects.

Example 3-15 Dosage Forms Having at Least One Tri-Oxy Active and atLeast One Oxyl-Containing Non-Ionic Hydrophilic Polymer

Tablet dosage forms having the compositions as recited in Examples 3through 15 are prepared by using the respective components shown inTables I and II.

TABLE I EXAMPLE INGREDIENT* 3 4 5 6 7 8 9 10 First Active (Tri-oxyactive), 54 54 54 54 54 54 54 54 mg [e.g. Codeine Phosphate, CP] SecondActive (Non-oxo 8 8 8 8 8 8 8 8 active), mg [e.g. ChlorpheniramineMaleate, CPM] Oxyl-containing non-ionic 25 75 200 450 65 85 — 50hydrophilic polymer, mg [e.g. Hypromellose 2208] Oxyl-containingnon-ionic — — — — — — 57 19 hydrophilic polymer, mg [e.g. Hypromellose2910] Pharmaceutical Processing 65 65 105 160 75 65 73 80 Aids, mg TotalMethoxyl Content of the 0.19 0.56 1.50 3.37 0.49 0.64 0.58 0.57non-ionic hydrophilic polymer, (mMol.) Total Hydroxyl Content of the0.13 0.40 1.08 2.42 0.35 0.46 0.31 0.37 non-ionic hydrophilic polymer(mMol.) Total Oxyl Content of the non- 0.32 0.97 2.57 5.79 0.84 1.090.89 0.94 ionic hydrophilic polymer (mMol.) Total Molar Content of the0.41 0.41 0.41 0.41 0.41 0.41 0.41 0.41 Oxygen Containing Groups inCodeine (mMol.) Ratio of the total molar content 0.78 2.38 6.30 14.22.06 2.67 2.17 2.30 of oxyl groups in the hydrophilic polymer to thetotal molar content of the oxygen containing groups in Codeine Phosphate*Excipients shown are exemplary of the classes; additionalPharmaceutical Processing aids known in the art can be used.

TABLE II EXAMPLE 11 12 13 14 15 INGREDIENT* mg mg mg mg mg First Active(Tri-oxy 27 54 54 54 40 active) [e.g. Codeine Phosphate, CP] SecondActive  4  8  8 — — (Non-oxo active) [e.g. Chlorpheniramine Maleate,CPM] Second Active — — — — 120  (Non-oxo active) [e.g. Pseudoephedrine,SUD] Second Active — — — 30-60 — (Non-oxo active) [e.g. Phenylephrine,PE] Third Active [e.g. — 120 — — — Pseudoephedrine, SUD] Third Active[e.g. — — 30-60 — — Phenylephrine, PE] Oxyl-containing non-ionic — 70-135  70-135  70-135  70-135 hydrophilic polymer [e.g. Hypromellose2208] Pharmaceutical Processing 155  55-80 55-80 55-80 55-80 Aids*Excipients shown are exemplary of the classes; additionalPharmaceutical Processing aids known in the art can be used.

Procedure for Preparing the Tablets of Examples 1 to 15 is as Follows

The actives are separately sifted through a clean ASTM Mesh No. 60 andthoroughly mixed by serial addition method. The actives are mixedthoroughly and the non-ionic hydrophilic polymer(s) are passed throughthe ASTM Mesh No. 60 and blended with the mixture of the actives. Thepowder admixture is blended with the previously sieved (ASTM mesh No.60) and collected pharmaceutical aids (diluents, lubricants etc) Theresulting powder blend is then compressed into tablets using 8 or 10 mmdiameter round die-punch tooling fitted to a single stroke tabletcompression machine, keeping the hardness of tablets in the range ofabout 4-9 kP.

Example 11 is an immediate release tablet manufactured either by dryblending or conventional wet granulation and compression process andwherefrom about 80% by weight or more of both the actives was releasedwithin about 30 minutes when tested in vitro as described above. Itshould be noted that the above said compositions can be also processedto get tablets by the conventional wet-granulation method known in theart. Accordingly, an aqueous solution of the binder in which the wettingagent(s) may also be included, is employed to granulate an admixture ofthe actives, filler and the polymer(s). The wet granulate is dried,sized, lubricated and compressed to tablets. The in vitro drug releasetesting procedure for the above disclosed example dosage forms isdescribed in Example 1. The calculated release profiles of the activesfrom some of the representative example dosage forms are shown in TableIII and FIG. 1.

TABLE III Example 3 4 5 6 11 12 ACTIVE CP CPM CP CPM CP CPM CP CPM CPCPM CP CPM SUD Mean T_(25%,) hours 0.3 0.3 0.5 0.5 1.0 1.0 1.1 0.9 <0.3<0.3 0.5 0.4 0.5 Mean T_(50%,) hours 0.9 0.9 1.8 1.9 3.5 3.3 4.9 4.3<0.5 <0.5 1.7 1.8 1.9 Mean T_(75%,) hours 1.9 2.0 3.9 4.0 7.3 7.1 11.310.1 <0.7 <0.7 3.7 4.0 4.2 CP = Codeine Phosphate; CPM =Chlorpheniramine Maleate; SUD = Pseudoephedrine

Unlike Examples 3, 5, 6 and 11, Example 4 of the invention providesoptimal release for a 12 hour product. Notably, Example 4 has a ratio oftotal molar content of the oxyl groups in the hydrophilic polymer to thetotal molar content of the oxygen-containing groups in the codeine about3.5, whereas Example 3 has the ratio less than 2.5 and Examples 5 and 6has the ratio greater than 9.0.

The tablet dosage forms of Examples 4, 5 and 6 were evaluated for invivo pharmacokinetic performance after a single dose administration incomparison to the IR tablet of Example 11, in 10-12 subjects. The studywas carried out similar way as presented in Example 2. The Tablets ofExamples 4, 5 and 6 were administered once, while the tablet of Example11 was administered every six hours, for 12 hours (i.e. twice in 12hours). The total dose of Codeine Phosphate was 54.3 mg in 12 hours andchlorpheniramine maleate was 8 mg. The plasma concentration of codeineand chlorpheniramine was determined by LC-MS/MS method.

Table IV shows the results of the pharmacokinetic parameters for each ofthe actives of Examples 4, 5 and 6 expressed as a percentage of itsratio to the corresponding parameters obtained for respective activesgiven as IR tablet (Example 11) every 6 hours, twice. However it isnoteworthy that the IR tablet can be given as a single combinationtablet (as Example 11) or as co administered single active tablets.

TABLE IV EXAMPLE 4 5 6 ACTIVE CP CPM CP CPM CP CPM Mean % C_(max)(ng/ml) 88.9 85.3 64.2 70.6 53.1 64.0 Mean % AUC₀₋₁₂ 101.7 95.2 83.073.1 70.7 65.4 (ng · h/ml) Mean % AUC_(inf) 104.9 100.5 112.5 101.6110.1 92.7 (ng · h/ml) Mean % C₁₂ (ng/mL) 98.6 85.0 128.6 74.3 123.161.9

Unlike Examples 5 and 6, Example 4 of the invention provides optimalpharmacokinetic parameters for a 12 hour product. Notably, Example 4 hasa ratio of total molar content of the oxyl groups in the hydrophilicpolymer to the total molar content of the oxygen-containing groups inthe codeine about 3.5, whereas Examples 5 and 6 has the ratio greaterthan 9.0.

Example 16-32 Dosage Forms Having at Least One Tri-Oxy Active and atLeast One Oxyl-Containing Non-Ionic Hydrophilic Polymer

Tablet dosage forms of having the compositions as recited in Examples 16to 32 are prepared by using the respective components shown in Tables Vto VII. The tablet dosage forms are manufactured by a similar process asdescribed for Examples 3 to 15. Tablet dosage forms of Examples 23, 24and 25 were compressed to achieve a total Codeine Phosphate dose of 30mg per tablet and guaifenesin to 600 mg per tablet.

TABLE V EXAMPLE INGREDIENT* 16 17 18 19 20 21 22 First Active (Tri-oxyactive), mg 30 30 30 30 30 30 20 [e.g. Codeine Phosphate, CP] SecondActive (Tri-oxy active), 600 600 600 600 600 600 400  mg [e.g.Guaifenesin, GGE] Oxyl-containing non-ionic 20 65 105 185 105 220 —hydrophilic polymer, mg [e.g. Hypromellose 2208] PharmaceuticalProcessing Aids, 60-100 60-100 60-100 60-100 75-140 60-100 55 mg TotalMethoxyl Content of the 0.15 0.49 0.79 1.39 0.79 1.65 — non-ionichydrophilic polymer (mMol.) Total Hydroxyl Content of the 0.11 0.35 0.571.00 0.57 1.18 — non-ionic hydrophilic polymer (mMol.) Total OxylContent of the non- 0.26 0.84 1.35 2.38 1.35 2.83 — ionic hydrophilicpolymer (mMol.) Total Molar Content of the 0.23 0.23 0.23 0.23 0.23 0.23— Oxygen Containing Groups in Codeine Phosphate (mMol.) Ratio of thetotal molar content of 1.15 3.71 5.96 10.51 5.96 12.50 — oxyl groups inthe hydrophilic polymer to the total molar content of the oxygencontaining groups in Codeine Phosphate Total Molar Content of the 12.1112.11 12.11 12.11 12.11 12.11 — Oxygen Containing Groups in Guaifenesin(mMol.) Ratio of the total molar content of 0.02 0.07 0.11 0.20 0.110.23 — oxyl groups in the hydrophilic polymer to the total molar contentof the oxygen containing groups in Guaifenesin *Excipients shown areexemplary of the classes; additional Pharmaceutical Processing aidsknown in the art can be used.

TABLE VI EXAMPLE 23 24 25 INGREDIENT* % w/w % w/w % w/w First Active(Tri-oxy active) 3.8-3.9 3.2-3.7 3.0-3.1 [e.g. Codeine Phosphate, CP]Second Active (Tri-oxy active) 76-79 64-74 59-62 [e.g. Guaifenesin, GGE]Oxyl-containing non-ionic 1-5  8-20 23-26 hydrophilic polymer [e.g.Hypromellose 2208] Pharmaceutical Processing Aids 15-16 13-15 11-12*Excipients shown are exemplary of the classes; additionalPharmaceutical Processing aids known in the art can be used.

TABLE VII EXAMPLE 26 27 28 29 30 31 32 INGREDIENT* (mg) (mg) (mg) (mg)(mg) (mg) (mg) First Active (Tri-oxy active) 30 30 30 30 30 30 30 [e.g.Codeine Phosphate, CP] Second Active (Tri-oxy active) 600  600  600 600  600  — — [e.g. Guaifenesin, GGE] Second Active (Non-oxo active) — —— — — 30 — [e.g. Dextromethorphan, DXM] Third Active — — — — 60 — 60[e.g. Pseudoephedrine, SUD] Third Active [e.g. Phenylephrine, — — —15-30  — 15-30 — PE] Oxyl-containing non-ionic 53 25 — 60-125 80-15060-150 80-150 hydrophilic polymer [e.g. Hypromellose 2208]Oxyl-containing non-ionic 40 10 80 — — — — hydrophilic polymer [e.g.Hypromellose 2910] Pharmaceutical Processing Aids 70-145 80-125 90-12090-120 90-120 90-120 90-120 *Excipients shown are exemplary of theclasses; additional Pharmaceutical Processing aids known in the art canbe used.

The in vitro for drug release testing procedure for the above exampledosage forms is described in Example 1. The calculated release profilesof the actives from some of the representative examples are shown inTable VIII and FIG. II. Example 22 is an immediate release tabletwherefrom about 80% by weight or more of both the actives was releasedwithin about 30 minutes when tested in vitro as previously described.

TABLE VIII EXAMPLE 16 17 18 19 22 ACTIVE GGE CP GGE CP GGE CP GGE CP GGECP Mean 0.20 0.30 0.5 0.3 0.8 0.6 1.4 0.9 <0.3 <0.3 T_(25%,) hours Mean0.70 0.80 2.2 1.9 3.0 2.4 4.4 3.3 <0.5 <0.5 T_(50%,) hours Mean 1.401.50 5.2 4.8 6.5 5.6 8.9 7.0 <0.7 <0.7 T_(75%,) hours, GGE =guaifenesin; CP = codeine phosphate

Unlike Examples 16 and 19, Examples 17 and 18 of the invention providesoptimal release for a 12 hour product. Notably, Examples 17 and 18 havea ratio of total molar content of the oxyl groups in the hydrophilicpolymer to the total molar content of the oxygen-containing groups inthe guaifenesin is between 0.07 about 0.18, whereas Example 16 has theratio less than 0.07 and Example 19 has the ratio greater than 0.18. Thetablet dosage forms of Examples 17, 18 and 19 were evaluated for in vivopharmacokinetic performance after a single dose administration incomparison to the IR tablet of Example 22, in 10-12 subjects. The studywas carried out in similar way as outlined in Example 2. In particular,the dosage forms of Example 17, 18 and 19 were administered once, whilethe dosage form of Example 22 was administered every four hours, for 12hours. (i.e. three times in 12 hours). The total dose of guaifenesin was1200 mg in 12 hours and codeine phosphate was 60 mg in 12 hours. Theplasma concentration of GGE and codeine were determined by LC-MS/MSmethod

Table VIII shows the results of the pharmacokinetic parameters for eachof the actives of Examples 17, 18 and 19 expressed as a percentage ofits ratio to the corresponding parameters obtained for respectiveactives given as IR tablet (Example 22) every 4 hours for 12 hours. Themean T_(max) is expressed as absolute value in hours for each activefrom respective examples. However it is noteworthy that the IR tabletcan be given as a single combination tablet (as Example 22) or as coadministered single active tablets.

TABLE IX EXAMPLE 17 18 19 GGE CP GGE CP GGE CP Mean % C_(max) (ng/ml)75.4 100.2 60.0 90.8 44.7 80.0 Mean % AUC₀₋₁₂ 91.7 97.3 89.8 98.1 86.399.8 (ng · h/ml) Mean % AUC 0-α 91.4 97.3 89.8 99.2 92.0 106.1 (ng ·h/ml) Mean % C₁₂ (ng/mL) 29.3 50.5 71.2 62.5 111 68.4 Mean T_(max)(hour) 2.0 4.0 2.0 4.0 2.0 4.0

It can be seen from Examples 17, 18 and 19, the criticality of the typeand the minimum and maximum levels of the non-ionic oxyl-containinghydrophilic polymer that is essential for enabling a product fordelivery once every 12 hours, for oxo-actives such as guaifenesin andcodeine. Notably, Examples 17 and 18 have a ratio of total molar contentof the oxyl groups in the hydrophilic polymer to the total molar contentof the oxygen-containing groups in the guaifenesin is between 0.07 about0.18, whereas Example 19 has the ratio greater than 0.18. Furthermore,Table X gives the absolute C_(max) and C_(min) value of the dosage formsof invention upon steady state simulation. For the purpose ofsimulations, dosage forms of Examples 17 are 18 are administered twotablets every 12 hours.

TABLE X EXAMPLE 17 18 ACTIVE GGE CP GGE CP Mean C_(max) (ng/mL) 134259.2 1153 56.9 Mean C_(minss) (ng/mL) 56 15.7 136 19.8Examples 17 and 18 of the invention provides optimal pharmacokinetic fora 12 hour product.

Examples 33-48 Dosage Forms Having at Least One Tri-Oxy Active and atLeast One Oxyl-Containing Non-Ionic Hydrophilic Polymer

Tablet dosage forms of having the compositions as recited in Examples 27through 38 are prepared by using the respective components shown inTables XI to XIII. The in vitro for drug release testing procedure forthe said example dosage forms is described in Example 1. The releaseprofiles of the actives from some of the representative examples areshown in Table-XIV and FIG. III. Examples 38 and 39 are immediaterelease tablets of hydrocodone bitartrate (HB) and GGE respectively andwhich release about 80% by weight or more of the active within about 30minutes when tested in vitro as previously described.

Example 38 is a commercially available hydrocodone bitartrate IR tablet(e.g. Hycodan®, Endo Pharmaceuticals) and it contains an additionalactive homatropin methyl bromide. IR Tablets of guaifenesin andhydrocodone bitartrate (Examples 38 and 39, respectively) togetherconstitute as reference product for comparison of the said exampledosage forms of the current invention.

TABLE XI EXAMPLE INGREDIENT* 33 34 35 36 37 38^(#) 39 First Active(Tri-oxy active), mg 600 600 600 600 600 — 400 [e.g. Guaifenesin, GGE]First Active (Tri-oxy active), mg 5 5 5 5 5 5   — [e.g. HydrocodoneBitartrate, HB] Homatropine Methylbromide, mg — — — — — 1.5 —Oxyl-containing non-ionic 25 65 145 185 105 — — hydrophilic polymer, mg[e.g. Hypromellose 2208] Pharmaceutical Processing Aids, 45 40-65 40-6540-65 50-120 50-150 50-70 mg Total Methoxyl Content of the 0.19 0.491.09 1.39 0.79 — — non-ionic hydrophilic polymer (mMol.) Total HydroxylContent of the 0.13 0.35 0.78 1.00 0.57 — — non-ionic hydrophilicpolymer (mMol.) Total Oxyl Content of the non- 0.32 0.84 1.87 2.38 1.35— — ionic hydrophilic polymer (mMol.) Total Molar Content of the 12.1112.11 12.11 12.11 12.11 — — Oxygen Containing Groups in Guaifenesin(mMol.) Ratio of the total molar content of 0.03 0.07 0.15 0.20 0.11 — —oxyl groups in the hydrophilic polymer to the total molar content of theoxygen containing groups in Guaifenesin *Excipients shown are exemplaryof the classes; additional Pharmaceutical Processing aids known in theart can be used. ^(#)Commercially available hydrocodone bitartrate IRtablet (e.g. Hycodan ®)

TABLE XII EXAMPLE 40 41 42 INGREDIENT* % w/w % w/w % w/w First Active(Tri-oxy active) 78-82 66-76 62-63 [e.g. Guaifenesin, GGE] First Active(Tri-oxy active) 0.7 0.5-0.6 0.5 [e.g. Hydrocodone Bitartrate, HB]Oxyl-containing non-ionic 1-5  8-20 23-27 hydrophilic polymer [e.g.Hypromellose 2208] Pharmaceutical Processing Aids 16   13-15 11-13*Excipients shown are exemplary of the classes; additionalPharmaceutical Processing aids known in the art can be used.

TABLE XIII EXAMPLE 43 44 45 46 47 48 INGREDIENT* (mg) (mg) (mg) (mg)(mg) (mg) First Active (Tri-oxy active) 600  600 190 600  600  600 [e.g. Guaifenesin, GGE] First Active (Tri-oxy active)  5  5 —  5  5  5[e.g. Hydrocodone Bitartrate, HB] Second Active (Non Oxo — — — 30 — 30Containing) (e.g. Dextromethorphan) Third Active — — — 60 — — [e.g.Pseudoephedrine, SUD] Third Active [e.g. Phenylephrine, — — — — 15-30 15-30  PE] Oxyl-containing non-ionic 73 — — 80-150 80-150 80-150hydrophilic polymer [e.g. Hypromellose 2208] Oxyl-containing non-ionic55 110 — — — — hydrophilic polymer [e.g. Hypromellose 2910]Pharmaceutical Processing Aids 90-120 40-65 90-120 50-120 50-120 50-120*Excipients shown are exemplary of the classes; additional tabletingaids known in the art can be used.

TABLE XIV Example 33 34 35 36 38 39 ACTIVE GGE HB GGE HB GGE HB GGE HBHB GGE Mean 0.2 0.3 0.6 0.5 1.0 1.0 1.3 1.3 <0.3 <0.3 T_(25 %,) hoursMean 0.6 0.7 1.9 1.5 3.1 2.9 4.0 4.1 <0.5 <0.5 T_(50 %,) hours Mean 1.41.4 4.0 3.3 6.3 5.6 7.5 7.3 <0.7 <0.7 T_(75 %,) hours, GGE =guaifenesin; HB = hydrocodone bitartrate

Unlike Examples 33, 36, 38 and 39, Examples 34 and 35 of the inventionprovides optimal release for a 12 hour product. Notably, Examples 34 and35 have a ratio of total molar content of the oxyl groups in thehydrophilic polymer to the total molar content of the oxygen-containinggroups in the guaifenesin is between 0.07 about 0.18, whereas Example 33has the ratio less than 0.07 and Example 36 has the ratio greater than0.18

The tablet dosage forms of Examples 33, 34 and 35 were evaluated for invivo pharmacokinetic performance after a single dose administration incomparison to the Guaifenesin IR tablet(s) of Example 39 and hydrocodonebitartrate IR tablet (e.g. Hycodan®, Example 38), in 10-12 subjects. Thestudy was carried out as outlined in Example 2. Specifically, the dosageforms of Examples 33, 34 and 35 were administered once, whileGuaifenesin IR tablet was given every four hours for 12 hours, and thehydrocodone bitartrate IR reference tablet given every six hours for 12hours. The total dose of Guaifenesin was 1200 mg in 12 hours and ofhydrocodone bitartrate was 10 mg in 12 hours. The plasma concentrationof GGE and hydrocodone were determined by LC-MS/MS method.

Table XV shows the results of the pharmacokinetic parameters for each ofthe actives of Examples 33, 34 and 35 expressed as a percentage of itsratio to the corresponding parameters obtained for respective activesgiven as IR tablets (Examples 31 and 32 every four hours and every 6hours respectively, for 12 hours. The absolute minimum plasmaconcentrations at steady state for guaifenesin and hydrocodone from theadministered dosage forms of some examples of this invention are shownin Table XVI.

TABLE XV EXAMPLE 33 34 35 ACTIVE GGE HB GGE HB GGE HB Mean % C_(max)(ng/ml) 75.4 100.2 60.0 90.8 44.7 80.0 Mean % AUC₀₋₁₂ 95.3 108.0 90.3102.9 74.1 94.9 (ng · h/ml) Mean % AUC_(inf) (ng · h/ml) 91.4 97.3 89.899.2 92.0 106.1 Mean % C₁₂ (ng/mL) 30.2 50.7 70.8 63.6 87.2 67.5 MeanT_(max) (h) 1.3 2.8 2.0 4.0 2.0 4.0

Unlike Example 33, Examples 34 and 35 of the invention provides optimalpharmacokinetic for a product formulated for delivery once every 12hours. Notably, Examples 34 and 35 have a ratio of total molar contentof the oxyl groups in the hydrophilic polymer to the total molar contentof the oxygen-containing groups in the guaifenesin is between 0.07 about0.18, whereas Example 33 has the ratio less than 0.07

TABLE XVI EXAMPLE 33 34 35 ACTIVE GGE GGE GGE Mean C_(minss) 1.85 14.122.8 (ng/mL)As it can be seen from Examples 34 and 35 have acceptable Mean C_(minss)(ng/mL) value of greater than 3 ng/mL for 12 hour product.

Example 49 Coated Pharmaceutical Tablets

The tablet dosage forms of Examples 3 to 10, 12 to 15, 16-21, 23-32,33-37 and 40 to 48 can be further coated with a coating solution havingtypical composition set forth in Table XVII, using conventional tabletcoating procedures known in the art to a weight gain of about 2 to 6%.

TABLE XVII INGREDIENT* Composition in % w/w Film coating polymer (e.g.Methocel E 5) 8.0 Plasticizer (e.g. Polyethylene glycol, NF 8000) 0.6Coating Solvent (e.g. Ethanol) 54.8 Coating Solvent Water 36.6*Excipients shown are exemplary of the classes; additionalpharmaceutical processing aids known in the art can be used.

Examples 50-51 In Vitro Release of Actives from Exemplary Embodiments

Tablet dosage forms of having combination of the oxo-actives (e.g.guaifenesin, codeine phosphate etc.) in the compositions as recited inExamples 50 and 51 are prepared by using the respective components shownin Tables XVIII. The in vitro drug release testing procedure for thesaid example dosage forms is described in Example 1. The releaseprofiles of the actives from some of the representative formulations areshown in Table-XIX. Example 50 contains the oxyl-containing non-ionichydrophilic polymer within the range disclosed in the invention, whileExample 51 does not contain polymer within the range disclosed in theinvention.

TABLE XVIII EXAMPLE 50 51 INGREDIENT* (mg) (mg) First Active (Tri-oxyactive) 30 30 [e.g. Codeine Phosphate, CP] Second Active (Tri-oxyactive) 600 600  [e.g. Guaifenesin, GGE] Oxyl-containing non-ionichydrophilic 105 — polymer [e.g. Hypromellose 2208] Oxyl-containingnon-ionic hydrophilic — 15 polymer [e.g. Hypromellose 2910]Pharmaceutical Processing Aids 65-100 65-105 *Excipients shown areexemplary of the classes; additional Pharmaceutical Processing aidsknown in the art can be used.

TABLE XIX Example 50 51 GGE CP GGE CP Mean T_(25%,) 0.84 0.55 1.00 0.85hours Mean T_(50%,) 3.01 2.40 3.90 3.60 hours Mean T_(75%,) 6.51 5.578.00 7.12 hours,

Unlike Example 51, Example 50 of the invention provides optimal releasefor a 12 hour product. The tablet dosage forms of Examples 50 and 51were evaluated for in vivo pharmacokinetic performance after a singledose administration of two (2) tablets each. Table XX shows the absolutevalues of the pharmacokinetic parameters for guaifenesin.

TABLE XX EXAMPLE 50 51 GGE GGE Mean C_(max) (ng/ml) 1050 821

Unlike Example 51, Example 50 of the invention provides greater C_(max)for a 12 hour product.

Example 52 Food Effect Pharmacokinetics

The tablet dosage forms of Example 18, the IR tablets of Example 22 wereevaluated for Effect of food on in vivo pharmacokinetic performanceafter a single dose administration to 10 subjects. Accordingly, thetablet of Example 18 (Test formulation) administered either afterovernight fasting or within 30 minutes of administration of food.Similarly, in another group, the IR tablets of Example 22 (Referenceformulation) were given either after overnight fasting or within 30minutes of administration of food. The plasma analysis for guaifenesinand codeine were carried out by LC-MS/MS. The PK parameters areexpressed as a ratio to the corresponding parameters obtained for eachdosage form after administration with food or under fasted state.

It was observed that a there was no significant food effect seen forguaifenesin and codeine from the Example 18 tablets. On the contrary,the IR tablets exhibited a significant food effect wherein, the plasmaguaifenesin C_(max) was significantly low when administered with foodcompared to when given under fasted conditions, as shown in the TableXXI & XXII wherein the ratios of the fed-to-fasted PK results forguaifenesin are given.

TABLE XXI Example 18 Example 22 ACTIVE GGE CP GGE Mean % C_(max) ratio(fed/fasted) (ng/ml) 102 127 67 Mean % AUC_(last) ratio (fed/fasted) (ng· h/ml) 98 109 89 Mean % AUC_(0-α) ratio (fed/fasted) 96 104 89 (ng ·h/ml)

Unlike the Example 22, Example 18, containing appropriate level ofoxyl-containing non-ionic hydrophilic polymer, is less sensitive to foodeffect.

Example 53-54 Effect of Oxyl-Containing Non-Ionic Polymer in Comparisonto Ionic Polymer on Food Effect Pharmacokinetic Study

Tablet dosage forms according to the current invention havingcombination of oxo-actives (e.g. guaifenesin and Codeine phosphate) inthe compositions as recited in Examples 53 and 54 shown in Table XIXwere evaluated for food effect pharmacokinetics on similar lines asdescribed under Example 52. While dosage form of Example 53 containsonly oxyl-containing non-ionic hydrophilic polymer within the rangedisclosed in the invention, the Example 54 has ionic hydrophilic polymeralong with oxyl-containing non-ionic hydrophilic polymer.

TABLE XXII EXAMPLE 53 54 Ingredient* (mg) (mg) First Active (Tri-oxyactive) 30 30 [e.g. Codeine Phosphate, CP] Second Active (Tri-oxyactive) 600 600 [e.g. Guaifenesin, GGE] Oxyl-containing non-ionichydrophilic 105 15 polymer [e.g. Hypromellose 2208 or Hypromellose 2910]Ionic Hydrophilic Polymer [e.g. Carbopol — 7.5 974P] PharmaceuticalProcessing Aids 75-120 65-85 *Excipients shown are exemplary of theclasses; additional Pharmaceutical Processing aids known in the art canbe used.

The dosage form of Example 53 showed no food effect on C_(max),AUC_(0-inf). On the contrary, the ionic polymer containing formulationsimilar to Example 54 is prone to food effect, probably due to the ionicnature of the polymer, which is known to be sensitive to pH changes inthe presence of food.

1. A method of treatment, said method comprising: administering to an individual having cough or cold, twice a day, a pharmaceutical composition which is a solid tablet comprising 54 mg of codeine phosphate and 8 mg chlorpheniramine maleate or a pharmaceutically acceptable salt of chlorpheniramine; said method providing (i) a mean AUC_(inf) of codeine and chlorpheniramine that is 70% to 135% of the respective mean AUC_(inf) provided by an immediate release dosage administered to a subject under fasted conditions every 4 to 6 hours over a 12 hour time period, where the cumulative dosage amount administered over the 12 hour time period of codeine and chlorpheniramine in the immediate release oral dosage is equivalent to the respective amount in said pharmaceutical composition; and wherein (ii) the variation in a pharmacokinetic parameter for codeine and chlorpheniramine in the oral dosage form is not more than about 40% as compared to the same pharmacokinetic parameter measured in the same subject when the pharmaceutical composition is administered under fed versus fasted condition.
 2. The method of claim 1 wherein said pharmaceutical composition comprises a release rate controlling non-ionic oxyl-containing hydrophilic polymer.
 3. The method of claim 2 wherein the ratio of total molar content of oxyl groups in the release rate controlling non-ionic oxyl-containing hydrophilic polymer to the total molar content of the oxygen groups in the codeine is about 2.5 to about 9.0.
 4. The method of claim 1 wherein single dose administration of the pharmaceutical composition provides therapeutic levels of codeine, chlorpheniramine, or both, for about 12 hours.
 5. The method of claim 1 wherein single dose administration of the pharmaceutical composition provides cough or cold symptom relief for about 12 hours.
 6. The method of claim 1 that allows the subject to sleep through the night or minimizes sleep disturbances.
 7. The method of claim 1 wherein a single-dose administration to a subject under fasted conditions provides a mean C_(max) for each of codeine and chlorpheniramine that is 70% to 135% of a respective mean C_(max) provided by administering an immediate release oral dosage form to a subject under fasted conditions every 4 to 6 hours over a 12 hour time period, wherein cumulative dosage amount administered over the 12 hour time period of codeine and chlorpheniramine in the immediate release oral dosage is equivalent to the respective amount of codeine and chlorpheniramine in said pharmaceutical composition.
 8. The method of claim 1 wherein said pharmaceutical composition further comprises pseudoephedrine.
 9. A method for minimizing sleep disturbances or allowing for sleeping through the night said method comprising: administering to an individual in need of minimizing sleep disturbance or allowing for sleeping through night a pharmaceutical composition comprising 54 mg of codeine and 8 mg chlorpheniramine maleate or an equivalent amount of a pharmaceutically acceptable salt of chlorpheniramine and a release rate controlling non-ionic oxyl-containing hydrophilic polymer.
 10. The method of claim 9 wherein the ratio of total molar content of oxyl groups in the release rate controlling non-ionic oxyl-containing hydrophilic polymer to the total molar content of the oxygen groups in the codeine is about 2.5 to about 9.0.
 11. The method of claim 9 wherein said pharmaceutical composition is administered before bedtime.
 12. The method of claim 9 wherein a single-dose administration to a subject under fasted conditions provides a mean C_(max) for each of codeine and chlorpheniramine that is 70% to 135% of a respective mean C_(max) provided by administering an immediate release oral dosage form to a subject under fasted conditions every 4 to 6 hours over a 12 hour time period, wherein the cumulative dosage amount administered over the 12 hour time period of codeine and chlorpheniramine in the immediate release oral dosage is equivalent to the respective amount of codeine and chlorpheniramine in said pharmaceutical composition.
 13. The method of claim 9 wherein said pharmaceutical composition when placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., the time to release about 50% of the amount of codeine and chlorpheniramine is about 1.5 to 3 hour.
 14. The method of claim 9 wherein said pharmaceutical composition is formulated such that when placed in a USP type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., the ratio of the amount of codeine released to the chlorpheniramine released at a single time point between 1 hour and 4 hour is from about 0.8:1 and about 1.2:1.
 15. The method of claim 9 wherein single dose administration of the pharmaceutical composition provides therapeutic levels of codeine, chlorpheniramine, or both for about 12 hours.
 16. The method of claim 9 wherein the release rate controlling non-ionic oxyl-containing hydrophilic polymer is hydroxypropyl methyl cellulose (HPMC) has an average methoxy content of about 15 mole % to about 30 mole %.
 17. The method of claim 9 wherein said pharmaceutical composition further comprises pseudoephedrine.
 18. A method for treating a subject, said method comprising administering to a subject a pharmaceutical composition having codeine and chlorpheniramine, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides therapeutic levels of codeine and chlorpheniramine to said subject for about twelve hours and wherein said pharmaceutical composition has two, three, four, or five of the following characteristics: (i) single-dose administration to a subject under fasted conditions provides a mean C_(max) for each of codeine and chlorpheniramine that is 70% to 135% of the respective mean C_(max) provided by administering an immediate release oral dosage form to a subject under fasted conditions every 4 to 6 hours over a 12 hour time period, wherein the cumulative dosage amount administered over the 12 hour time period of codeine and chlorpheniramine in the immediate release oral dosage is equivalent to the respective amount of codeine and chlorpheniramine in said pharmaceutical composition; (ii) single-dose administration to a subject under fasted conditions every twelve hours provides a mean C_(max) for each of codeine and chlorpheniramine that is 70% to 135% of the respective mean C_(max) provided by administering the same oral dosage to the subject under fed conditions every twelve hours; (iii) single-dose administration to a subject under fed conditions provides a mean C_(max) for each of the codeine and the chlorpheniramine that is 70% to 135% of a respective mean C_(max) provided by administering an immediate release oral dosage to a subject under fed conditions every 4 to 6 hours over a 12 hour time period, wherein the cumulative dosage amount administered over the 12 hour time period of codeine and chlorpheniramine in the immediate release oral dosage is equivalent to the respective amount of codeine and chlorpheniramine in the pharmaceutical composition; (iv) when placed in a USP type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at 37° C., the ratio of the amount of codeine released to the chlorpheniramine released at a single time point between 1 hour and 4 hour is from about 0.8:1 and about 1.2:1; (iv) single-dose administration to a subject under fasted conditions, provides a mean T_(max) for codeine in the range of about 2.2 hours to about 3.4 hours and a mean T_(max) for chlorpheniramine in the range of about 5 hours about 14 hours; (v) further comprises a release rate controlling non-ionic oxyl-containing hydrophilic polymer; and (vi) the codeine is resin free or pharmaceutical composition is resin free.
 19. The method of claim 14 wherein said method provides for relief of cough or cold.
 20. The method of claim 14 wherein said pharmaceutical composition allows the subject to sleep through the night or minimizes sleep disturbances.
 21. The method of claim 14 wherein said pharmaceutical composition is resistant to alcohol extraction.
 22. The method of claim 14 wherein said pharmaceutical composition further comprises a release rate controlling non-ionic oxyl-containing hydrophilic polymer.
 23. The method of claim 15 wherein said release rate controlling non-ionic oxyl-containing hydrophilic polymer has a total oxyl content of from about 4×10⁻⁴ mole to about 2.0×10⁻³ mole.
 24. The method of claim 22 wherein the ratio of total molar content of oxyl groups in the release rate controlling non-ionic oxyl-containing hydrophilic polymer to the total molar content of the oxygen groups in the codeine is about 2.5 to about 9.0.
 25. The method of claim 14 wherein said pharmaceutical composition further comprises pseudoephedrine. 